Immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA) results in hematologic responses in 60–70% of severe aplastic anemia (SAA) patients and long-term survival among responders >80% (Young, Calado et al. 2006). With standard horse ATG (h-ATG) + CsA, success is limited because 1/3 of patients are unresponsive; 1/3 of responders relapse after achieving hematologic recovery; and clonal evolution to myelodysplasia occurs in 10–15% of cases. Retreatment success with rabbit ATG (r-ATG) in refractory patients has varied widely, from 30->70% (DiBona, Coser et al. 1999; Scheinberg, Nunez et al. 2006); for relapse, response to retreatment has been more consistent, at 50–60% (Schrezenmeier, Marin et al. 1993; Tichelli, Passweg et al. 1998; Scheinberg, Nunez et al. 2006). We hypothesized that the humanized anti-CD52 monoclonal antibody alemtuzumab (Campath) might be active in SAA due to its lymphocytotoxic properties and reported activity in various immune cytopenias (Willis, Marsh et al. 2001). At the Clinical Center of the National Institutes of Health, we tested alemtuzumab monotherapy in several research protocols for marrow failure. For refractory SAA, we conducted a prospective randomized study (starting in 2003) comparing r-ATG/CsA vs. alemtuzumab in patients unresponsive to initial h-ATG/CsA (www.clinicaltrials.govNCT00065260). Sample size was based on the primary endpoint, hematologic response at 6 months, through testing the proportions with 5% significance level and 80% power. A difference in response rate of 30% was hypothesized between these two regimens. Rabbit-ATG was administered at 3.5 mg/kg/day for 5 days with CsA to a trough of 200 – 400 ng/ml for 6 months, and alemtuzumab at 10 mg/d for 10 days, without CsA. In a recent interim analysis (25 patients in each arm), the response rate for each regimen was identical at 36% (95% CI, 15%-56%; p=1.00). The 1000-day survival was 86% (95% CI, 63%-95%) in the alemtuzumab arm and 65% (95% CI, 39%-82%) in the r-ATG arm (log-rank, p=0.25). Both regimens were well tolerated with no significant difference in serious adverse events between the two groups. Subclinical EBV and CMV reactivations commonly occurred after immunosuppressive therapy as described previously (Scheinberg, Fischer et al. 2007). Specific prophylactic or pre-emptive antiviral therapies were not instituted in any case. Based on this initial experience, we conducted a single arm open label trial investigating alemtuzumab in relapsed SAA (www.clinicaltrials.govNCT00195624). Sample size was calculated using a Two-Stage Minimax Design, based on the hypothesis that response to alemtuzumab would be >50%. After accruing 23 patients (first stage), hematologic response at 6 months (primary endpoint) was observed in 13 (56%; 95% CI, 37%-77%) and the study will proceed to the second stage. Based on the encouraging results in refractory and relapsed SAA, alemtuzumab was investigated in treatment-naïve patients in a study that randomized (1:1:1) among h-ATG/CsA, r-ATG/CsA, and alemtuzumab (www.clinicaltrials.govNCT00260689). After 16 patients were randomized to alemtuzumab, this arm of the study was discontinued at the recommendation of the DSMB as response was observed in only three patients and there were three early deaths. Alemtuzumab was also investigated in other settings in the context of these clinical trials. Of 13 patients unresponsive to r-ATG/CsA given as first line therapy, only one patient responded to rescue with alemtuzumab; and of 11 patients who were unresponsive to both h-ATG/CsA and r-ATG/CsA, response to alemtuzumab was observed in two (both responders had shown small but incremental improvement with each prior ATG course). Our results show that: 1) alemtuzumab is an active agent in SAA patients with relapsed or refractory SAA; 2) either r-ATG or alemtuzumab can rescue about 30% of patients unresponsive to initial h-ATG + CsA; 3) the response rate of alemtuzumab in relapsed SAA is comparable to the reported response rate of 50%-60% in this setting; 4) the salvage rate with alemtuzumab in those unresponsive to initial r-ATG/CsA appear low; and 6) alemtuzumab cannot be recommended as first line therapy of SAA outside of a clinical research protocol.
Off Label Use: Alemtuzumab in severe aplastic anemia.
Asterisk with author names denotes non-ASH members.